The present invention relates to certain new derivatives of thiomarinol and provides processes for their preparation and methods and compositions using them as antibacterial agents.
Thiomarinol is described, for example, in European Patent Publication No. 512 824, published before the application date hereof but after the priority dates. It may be represented by the formula (A): ##STR1##
It is produced by fermentation by microorganisms of the genus Alteromonas, especially Alteromonas rava strain SANK 73390. We have now discovered two derivatives of thiomarinol, which have similar types of antibiotic activity to the original thiomarinol.
Organisms of the genus Alteromonas can be isolated from sea water, and some have been shown to produce compounds of potential therapeutic use. For example, a compound known as bisucaberin has been obtained from one species of Alteromonas, and has been shown to exhibit antitumor activity (Japanese Patent Kokai Application Number Sho 63-27484).
With respect to the structure of thiomarinol, several antibiotic substances having similar structures are known, and these may be divided into four groups.
The first group comprises the pseudomonic acids, first isolated from Pseudomonas spp. These include pseudomonic acid A [produced by Pseudomonas fluorescens, disclosed in J. Chem. Soc. Perkin Trans. I, 294 (1977)], pseudomonic acid B [ibid, 318 (1977)], pseudomonic acid C [ibid, 2827 (1982)] and pseudomonic acid D [ibid, 2655 (1983)]. Pseudomonic acid A is marketed under the name "Bactroban" (Beecham, registered trade mark) in the form of a 2% dermatological ointment for antibacterial use. However, all of these prior art compounds have weaker antibacterial activities than do the thiomarinol derivatives of the present invention.
The second group of substances sharing a similarity of structure with the compounds of the invention comprises that group which includes the antibiotics holomycin [Helv. Chim. Acta, 42, 563 (1959)], pyrrothine [J. Am. Chem. Soc., 77, 2861 (1955)], thiolutin [Angew. Chem., 66, 745 (1954)], aureothricin [J. Am. Chem. Soc., 74, 6304 (1952)], and others. These antibiotics are typically produced by actinomycetes, and are characterized by a sulfur-containing chromophore. Xenorhabdins I-V are substances related to holomycin, and have also been isolated from bacteria (disclosed in WO 84/01775).
Various studies on derivatives of these two groups have been performed, but we are not aware of any disclosure of a substance having a molecular structure similar to that of the thiomarinols, or which is characterized by similar properties.
The third group of compounds is disclosed in publications such as Japanese Application Kokai Numbers 52-102279, 54-12375, 54-90179, 54-103871 and 54-125672, which disclose pseudomonic acid derivatives wherein the terminal carboxylic acid is replaced by an amide group. These compounds do not exert comparable antibacterial activity and do not exhibit a broad spectrum of antibacterial activity. In fact, these compounds demonstrate a tendency to possess weaker antibiotic activity than that of the original pseudomonic acid.
The fourth group comprises a compound similar to thiomarinol in that it is a physiological substance of marine bacterial origin [Abstracts of Papers from the 200 Year Conference of the Am. Chem. Soc. (August 26-31, 1990), Part 2, ORGN. No. 139]. However, the heterocyclic group bonded to the terminal carbonyl group of this compound is a 2-oxo-3-piperidyl group. It has recently been shown to have antimicrobial activity [Experimentia, Vol. 48, pages 1165-1169 (1992)].
However, the most relevant prior art is thought to be pseudomonic acid A, and all of the thiomarinols, that is the original thiomarinol, thiomarinol B and thiomarinol C, have significantly more potent antibacterial activity than does pseudomonic acid A.